Neoplastic diseases are characterized by the proliferation of cells which are not subject to normal cell growth and are a major cause of death in humans and other mammals. Cancer chemotherapy has not only provided new and more effective drugs to treat these diseases but has also demonstrated that drugs which disrupt the microtubule system of the cytoskeleton are effective in inhibiting the proliferation of neoplastic cells.
The microtubule system of eucaryotic cells is a major component of the cytoskeleton and is a dynamic assembly and disassembly wherein heterodimers of tubulin are polymerized and form microtubule. Microtubules play a key role in the regulation of cell architecture, metabolism, and division and in their dynamic state are critical to normal cell function. With respect to cell division, tubulin is polymerized into microtubules that form the mitotic spindle. The microtubules are then depolymerized when the mitotic spindle's use has been fulfilled. Accordingly, agents which disrupt the polymerization or depolymerization of microtubules, and thereby inhibit mitosis, comprise some of the most effective cancer chemotherapeutic agents in clinical use. Thus agents which have the ability to disrupt the microtubule system are useful for cancer treatment.
Certain cryptophycin compounds are disclosed in U.S. Pat. Nos. 4,946,835, 4,845,085, 4,845,086, and 4,868,208; however, compounds having greater metabolic stability and longer duration of action are desired for most therapeutic uses. Thus there is still a need for compounds which inhibit mitosis.